Background This study aimed to investigate whether the pretreatment platelet to lymphocyte ratio (PLR) is a significant prognostic factor in metastatic pancreatic ductal adenocarcinoma (PDAC). Methods A total of 134 histologically confirmed PDAC patients were included in our retrospective study. The data included treatment regimens, Karnofsky Performance Status (KPS), and PLR. Kaplan-Meier curves and univariate and multivariate Cox proportional hazards regression analyses were applied to identify the prognostic factors associated with overall survival (OS). Results We used the receiver operating characteristic (ROC) curve to set the cut-off value of the PLR. For the Kaplan-Meier analysis, the median overall survival in PDAC patients with a PLR of 123 or less was 19.7 months, whereas the values in those with a PLR greater than 123 was 13.7 months (P=0.014). PLR was a significant prognostic marker in the multivariate Cox model [hazard ratio (HR) =1.721, 95% CI: 1.162–2.550, P=0.007]. Conclusions The PLR pretreatment had potential as prognostic indicator in patients with metastatic PDAC.

113 Background: Although the clinical trial WJOG7112G was failed to prove weekly paclitaxel with trastuzumab in patients with HER2-positive gastric or gastro-esophageal junction (GEJ) cancer refractory to trastuzumab is better than paclitaxel alone, there are limited data concerning efficacy of continuing trastuzumab beyond first-line progression in the real world. Methods: This retrospective study included all consecutive patients with HER2-positive advanced gastric or GEJ adenocarcinoma who received a chemotherapy with trastuzumab in first-line, or second-line, or third-line therapy between 2010 and 2016 in Chinese People’s Liberation Army General Hospital. Progression-free survival (PFS) and overall survival (OS) were estimated from the initial chemotherapy. Results: A total of 67 patients (median age, 59 years; male, 71.6%) with HER-2 positive advanced gastric or GEJ adenocarcinoma treated with chemotherapy plus trastuzumab initially in first (n = 50), second (n = 13), or third (n = 4) line of therapy were included. The median OS of trastuzumab for initial first-line, second-line, or third-line treatment was 16.7 months, 14.2 months, and 13.2 months, respectively (P = 0.83). In patients initially using trastuzumab in first-line therapy, the continuation (n = 19) versus discontinuation (n = 31) of trastuzumab beyond first-line progression was significantly associated with an improvement of median PFS (3.4 versus 1.9 months; P = 0.02), but not OS (19.0 versus 16.4 months; P = 0.13). In the multivariate analysis including the ECOG PS, number of metastatic sites and chemotherapy regimen, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.77; 95% CI, 0.41-0.93; P = 0.04), but not OS (HR, 0.85; 95% CI, 0.56-1.22; P = 0.24). Conclusions: This study suggests that HER-2 positive advanced gastric or GEJ adenocarcinoma patients could benefit from trastuzumab no matter when they start receiving trastuzumab. The continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer for PFS, but not for OS. Large scale prospective randomized validation is warranted.

203 Background: Several studies have linked a decrease of carbohydrate antigen (CA) 19-9 to lengthened survival in pancreatic cancer. Experimental evidence supported that CA19-9 may be involved in platelet/tumor cell interactions. The object of this study was to correlate a decline in CA19-9 with survival according to platelet level in metastatic pancreatic cancer. Methods: A retrospective analysis of patients with histologically diagnosed metastatic pancreatic cancer was performed. CA19-9 serum concentration and platelet level was measured at baseline and every 6 weeks. Results: Total 174 metastatic pancreatic cancer patients with baseline and week-6 CA19-9 measurements were analyzed. Median follow-up from initial chemotherapy was 29.2 months, and median survival from initial chemotherapy was 6.7 months. Multivariate analyses confirmed an early decrease in CA19-9 concentrations of 25% after two cycles of chemotherapy were associated with a favorable survival compared with patients who did not have a decrease of 25% (HR = 0.56 [95% CI: 0.40-0.78]). The association of CA19-9 decrease with overall survival differed by platelet level ( Pinteraction < 0.001). Multivariable adjusted hazard rations for decrease in CA19-9 of 25% were 0.30 (0.18-0.49) in patients with low platelet level (PLT < 190 × 109/L) and 0.85 (0.53-1.35) in patients with high platelet level (PLT ≥ 190×109/L). Conclusions: In patients with MPC, 25% decrease at week-6 could be an early marker for prognosis. The association of CA19-9 decrease with pancreatic cancer survival is stronger in patients with platelet low tumors than platelet high tumors. Our findings suggest a differential prognostic effect of CA19-9 according to platelet level.

Abstract Chemotherapy‐induced neutropenia (CIN) has been shown to be associated with improved clinical outcomes in patients with various solid tumors. This study retrospectively assessed the association between timing of CIN and prognosis in 321 patients with advanced gastric cancer (AGC) who finished at least one cycle of chemotherapy with oxaliplatin and capecitabine (XELOX). Primary landmark analyses were restricted to 274 patients who received four cycles of chemotherapy and lived for more than 4 months. CIN was categorized as early‐onset and non‐early‐onset. The correlation between timing of CIN with survival was analyzed by the Kaplan‐Meier method and a Cox proportional hazards model. Relative to patients with non‐early‐onset CIN, those with early‐onset CIN had significantly longer times to disease progression (hazard ratio [HR] 0.574; 95% confidence interval [CI] 0.453–0.729, P < 0.001) and death (HR: 0.607; 95% CI: 0.478–0.770, P < 0.001), consistent with results from the landmark group. In conclusion, timing of CIN may be a potential prognostic biomarker in patients with AGC receiving first‐line chemotherapy with XELOX. Early‐onset CIN predicts better survival.

Chemotherapy-induced neutropenia (CIN) was reported to be a predictor of better survival in several cancers. The objective of our study is to evaluate the relationship between the timing (onset) of CIN and prognosis. Between June 2008 and June 2015, 134 patients with confirmed advanced pancreatic cancer received at least one cycle of gemcitabine / gemcitabine-based chemotherapy as first-line chemotherapy were eligible for assessment. Timing of CIN was categorized into early onset and non-early onset CIN group. The end of cycle 2 was the cutoff to differentiate early onset or non-early onset. The correlation between timing of CIN with survival was analyzed by Kaplan-Meier method and Cox proportional hazards model. Median overall survival (OS) was 8.05 months (95% CI: 5.97-10.13) for patients with early onset CIN compared with 5.82 months (95% CI: 5.00-6.63) for patients without early-onset neutropenia (P = 0.022). Multivariate analysis proved that timing of CIN was an independent prognostic factor, hazard ratios of death was 0.696 (95% CI: 0.466-0.938) for patients with early onset CIN. In conclusion, timing of CIN is an independent predictor of prognosis in patients with advanced pancreatic cancer undergoing gemcitabine / gemcitabine based chemotherapy. Early-onset CIN predicts better survival.

Objective: In this study, we investigated the correlation between the degree and timing of chemotherapyinduced neutropenia (CIN) caused by the DCF (docetaxel-platinum-fluorouracil) regimen as first-line chemotherapy and the survival of patients with advanced gastric cancer. Methods: We retrospectively analysed 110 patients diagnosed with advanced gastric cancer between 2007 and 2012 at our hospital who received 2 to 6 cycles of the DCF regimen as first-line chemotherapy. According to the CTCAE 4, CIN is categorized as G0, G1/2, G3, or G4. We stratified all patients into the following two groups based on the onset (timing) of CIN: early onset and late onset. Results: A total of 110 patients were included in this study. Among these patients, 15 (13.6%) did not exhibit CIN (grade 0), 54 (49.1%) experienced mild CIN (grade 1-2), 22 (20.0%) developed moderate CIN (grade 3), and 19 (17.3%) suffered from severe CIN (grade 4) during the first line of chemotherapy. The median progression-free survival (PFS) of the 110 patients was 6.0 months (95% CI: 5.5~6.6 months), and the median overall survival (OS) of the 110 patients was 12.7 months (95% CI: 11.2~14.2 months). According to a multivariate analysis, the hazard ratio of death was 0.59 (95% CI: 0.49-0.72, P=0.005) for patients with G1/2 CIN, 0.71 (95% CI: 0.52-0.90, P=0.001) for patients with G3 CIN, and 0.74 (95% CI: 0.46-0.93, P=0.023) for patients with G4 CIN compared with patients who did not suffer from neutropenia (G0). Conclusion: Patients who experienced G1/2 CIN had a more favourable treatment response and prognosis, whereas the absence of CIN predicted poor efficacy and survival, which may occur because the dose was ineffective. In addition, patients with G4 CIN did not exhibit better efficacy and prognosis, and the clinical outcomes were better for early-onset neutropenia than for late-onset neutropenia.

The neutrophil-lymphocyte ratio (NLR) has been reported to be associated with prognosis in several cancers. The objective of our study was to evaluate the prognostic role of baseline NLR and change in NLR (ΔNLR) in advanced pancreatic cancer underwent chemotherapy. Between January 2010 and June 2015, 132 patients underwent chemotherapy were eligible for assessment. Based on our patients' data, the cut-off value of NLR was 2.78 according to receiver operating characteristic curve. We observed that a high level of baseline NLR (NLR > 2.78) was a poor prognostic factor for overall survival (multivariable hazard ratio [HR] = 2.648, P < 0.001). Increased NLR (ΔNLR > 0) after 2 cycles of chemotherapy was associated with higher risk compared to ΔNLR ≤ 0 (multivariable HR = 1.894, P = 0.007). Combining both NLR and ΔNLR factors, multivariate analysis showed a significant higher risk (HR = 5.817, P < 0.001) for patients with high baseline NLR and increased NLR after 2 cycles of chemotherapy compared to patients with low baseline NLR and ΔNLR ≤ 0. In conclusion, both baseline NLR and ΔNLR are independent prognostic predictors for patients with advanced pancreatic cancer underwent chemotherapy.

Hypoxia plays a vital role in tumor metabolism, proliferation, apoptosis, invasion and metastasis via hypoxia-inducible factor (HIF). Epithelial to mesenchymal transition (EMT) is a crucial process to metastasis, which could be triggered by hypoxia. EMT could be regulated by HIF via multiple pathways including TGF-β, Notch, and Wnt/β-catenin. It has been shown that anti-HIF drugs combined with anti-EMT therapies could be a promising strategy for tumor therapy.

In vitro tests for assessing the toxigenicity of strains of C. diphtheriae using the original agar plate precipitin method of Elek are unreliable. At high concentrations of antitoxin (500–1000 U/ml) multiple non-specific precipitin lines occur making interpretation difficult. Increased specificity was obtained by diluting the antitoxin but this in turn caused a delay in the appearance of toxin-antitoxin lines. Also. the failure of lines to appear on media enriched with unsuitable serum may lead to false-negative results. Final assessment of the toxigenicity of strains of C. diphtheriae can probably only be made reliably by guinea-pig tests.

Objective To investigate the correlation between the degree of chemotherapy-induced neutropenia (CIN) caused by the first line DCF scheme and the curative effect and survival in patients with advanced gastric cancer.Methods Clinical data about 110 patients diagnosed with advanced gastric cancer from 2007 to 2012 in our hospital who underwentfirst-line chemotherapy of DCF regimen at least 2 cycles were retrospectively analyzed. According to the CTCAE 4, CIN was divided into: G0, G1/2, G3, G4 group. The association between CIN and chemotherapy curative effect and prognosis was assessed.Results The multivariate analysis showed that compared with G0 group, the hazard ratio of disease-progression was decreased by 48% (HR=0.52, 95%CI: 0.44 - 0.69, P=0.005) in G1/2 group, 31% (HR=0.69, 95%CI: 0.37 - 0.89,P=0.001) in G3 group and 25% (HR=0.75, 95% CI: 0.46 - 0.98,P=0.023) in G4 group. Similarly, the hazard ratio of death was decreased by 41% (HR=0.59, 95%CI: 0.49 - 0.72,P=0.001) in G1/2 group in comparison with G0 group, 29% (HR=0.71, 95%CI: 0.52 - 0.90,P=0.000) in G3 group, and 26% (HR=0.74, 95%CI: 0.46 - 0.93, P=0.009) in G4 group. The ORR value of G0, G1/2, G3, G4 group were 13.3%, 53.7%, 45.5%, 10.5%, respectively; The DCR value of G0, G1/2, G3, G4 group were 33.3%, 75.9%, 68.2%, 57.9%, respectively. Both ORR and DCR value of the four groups showed significantly statistical differences with the best efficacy showed in G1/2 group.ConclusionPatients who experience G1/2 CIN have a more favorable treatment response and prognosis, however, absence of CIN represents poor efficacy and survival, which suggests that patients in G0 group may not achieve the best effective dose. In addition, G4 CIN does not show better efficacy and prognosis. Therefore, monitoring of CIN is conducive to the early evaluation of curative effect and prognosis, and it is helpful in adjusting the dosage of chemotherapy drugs.

AbstractThe anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in metastatic breast cancer. However, resistance to trastuzumab is common. Heterodimerization between ErbB2 and other ErbBs may redundantly trigger cell proliferation signals and confer trastuzumab resistance. Here, we developed a bispecific anti-ErbB2 antibody using trastuzumab and pertuzumab, another ErbB2-specific humanized antibody that binds to a distinct epitope from trastuzumab. This bispecific antibody, denoted as TPL, retained the full binding activities of both parental antibodies and exhibited pharmacokinetic properties similar to those of a conventional immunoglobulin G molecule. Unexpectedly, TPL showed superior ErbB2 heterodimerization-blocking activity over the combination of both parental monoclonal antibodies, possibly through steric hindrance and/or inducing ErbB2 conformational change. Further data indicated that TPL potently abrogated ErbB2 signaling in trastuzumab-resistant breast cancer cell lines. In addition, we showed that TPL was far more effective than trastuzumab plus pertuzumab in inhibiting the growth of trastuzumab-resistant breast cancer cell lines, both in vitro and in vivo. Importantly, TPL treatment eradicated established trastuzumab-resistant tumors in tumor-bearing nude mice. Our results suggest that trastuzumab-resistant breast tumors remain dependent on ErbB2 signaling and that comprehensive blockade of ErbB2 heterodimerization may be an effective therapeutic avenue. The unique potential of TPL to overcome trastuzumab resistance warrants its consideration as a promising treatment in the clinic. Cancer Res; 73(21); 6471–83. ©2013 AACR.

Treatment of chronic hepatitis B virus (HBV) infection with interferon and viral reverse transcriptase inhibitor regimens results in poor viral clearance, loss of response, and emergence of drug-resistant mutant virus strains. These problems continue to drive the development of new therapeutic approaches to combat HBV. Here, we engineered a bispecific antibody using two monoclonal antibodies cloned from hepatitis B surface antigen (HBsAg)-specific memory B cells from recombinant HBsAg-vaccinated healthy volunteers. Next, we evaluated its efficacy in neutralizing HBV in HepaRG cells. This bispecific antibody, denoted as C4D2-BsAb, had superior HBV-neutralizing activity compared with the combination of both parental monoclonal antibodies, possibly through steric hindrance or induction of HBsAg conformational changes. Moreover, C4D2-BsAb has superior endocytotic characteristics into hepatocytes, which inhibits the secretion of HBsAg. These results suggest that the anti-HBsAg bispecific antibody may be an effective treatment method against HBV infection.

The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab-resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer.